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A study of the relationship between polycystic ovary syndrome and endometrial cancer

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OC Pillay,a LF Wong Te Fong,a JC Crow,b E Benjamin,c T Mould,d W Atiomo,e PA Menon,f AJ Leonard,a A Sharkey,f R Catalano,g P Hardimana

a University Department of Obstetrics and Gynaecology and b University Department of Histopathology, Royal Free and University College Medical School, London, UK c Department of Histopathology and d Department of Gynaecological Oncology, University College London Hospitals, London, UK e Department of Obstetrics and Gynaecology, Queen’s Medical Centre NHS Trust, Nottingham, UK f Department of Histopathology, St Thomas Hospital, London, UK g Department of Pathology, Tennis Court Road, University of Cambridge, Cambridge, UK

Polycystic ovary (PCO) syndrome is assumed to be a risk factor for endometrial cancer (EC), although with better prognosis compared with women with normal ovaries.

The prevalence of PCO syndrome was investigated in ovaries from 128 EC and 83 benign control cases. When aged <50 years, PCO syndrome was more prevalent in EC than in controls (62.5 versus 28.5%, P= 0.041). p53, Ki67, Bcl 2 and cyclin D1 were investigated immunohistochemically in EC in women with PCO syndrome (n= 11) or in women with normal ovaries (n= 16). Cyclin D1 expressing tumours tended to be more prevalent in women with PCO syndrome (36.4 versus 6.25%, P= 0.071). Microarray analysis indicated that the expression of several oncogenes was up/downregulated more than three-fold in endometrial hyperplasia (EH; n= 5) versus normal proliferative morphology (n= 5).

EC appears more prevalent in premenopausal women with PCO syndrome. The increased prevalence of cyclin D1 expressing tumours in them suggests that prognosis is no better than in women with normal ovaries. Oncogene expression is already dysregulated in EH in women with PCO syndrome.

The hypercoagulable state of pregnancy: reference range of thromboelastographic parameters in normal pregnancy

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H Maybury,a P Squire,a E Hille,b F Pierik,b S Pavord,c DJ Taylor,a J Waugha

a Reproductive Sciences Section, Department of Cancer Studies and Molecular Medicine, Leicester Royal Infirmary, Leicester, UK b TNO Quality of Life, JPB, Department of Reproduction & Perinatology, Leiden, The Netherlands c Department of Haematology, Leicester Royal Infirmary, Leicester, UK

Changes in the coagulation and fibrinolysis pathways have been described in pregnancy but have failed to correlate with adverse thromboembolic outcome. Thromboelastography is a unique technique, which measures global haemostatic function from a single sample of whole blood.

Our prospective cross-sectional study (n= 258) describes the gestation-specific 95% reference ranges for five thromboelastographic parameters (R, K, α, MA and CI) in uncomplicated pregnancy (as defined by strict recruitment and outcome criteria).

All the five parameters were statistically (P < 0.05) hypercoagulable compared with those in nonpregnant controls (n= 108) during the first trimester. A statistically significant (P < 0.05) progressive increase in hypercoagulability was seen across all three trimesters (e.g. [mean, 95% CI], MA—first trimester: 59.01, 58.06–59.97; second trimester: 60.57, 59.47–61.67; third trimester: 64.52, 63.40–65.63; controls: 57.2, 56.1–58.3).

To date, all published thromboelastographic data fail to appreciate the changes of normal pregnancy. Our reference data are the essential first step in exploring the use of thromboelastography in high-risk pregnancy.

Maternal influences on fetal body composition in late pregnancy assessed by three-dimensional ultrasound

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P Mahon, S Crozier, J Poole, H Inskip, C Cooper, K Godfrey, the Southampton Women’s Survey Study Group

MRC Epidemiology Resource Centre, University of Southampton, Southampton, UK

We acquired 350 volume datasets of fetal thighs at 34 weeks of gestation using 3D ultrasound, on which bone, muscle and subcutaneous fat/skin volumes were calculated. Bone and fat/skin volumes were similar in both genders, but muscle volume was greater in males (P= 0.001). Maternal body composition had been assessed by anthropometry prior to pregnancy, and this data were merged with the scan results. Bone, muscle and fat/skin volumes were greater in fetuses of taller women (P= 0.03, P= 0.007 and P= 0.06, respectively). Bone volume was not related to maternal arm muscle area or fatness, but fetal muscle and fat/skin volumes were greater in mothers with a larger arm muscle area (P < 0.0001 and P= 0.008, respectively) and greater fat (P= 0.003 and P < 0.0001, respectively). Fat/skin volume was greater in the fetuses of multiparous women (P= 0.048) but not bone or muscle volume. We conclude that 3D ultrasound can provide useful volume measurements in late gestation, reflecting maternal influences on fetal body composition.

RhoA, Rhoi, ROCK and MYPT—a pathway of uterine quiescence in pregnancy

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J Lartey,a A Gampel,b J Pawade,c H Mellor,b A López Bernala

a University of Bristol, Clinical Sciences South Bristol, Division of Obstetrics and Gynaecology, Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Bristol, UK b University of Bristol, Department of Biochemistry, School of Medical Sciences, University Walk, Bristol, UK c University of Bristol, Department of Pathology, Bristol Royal Infirmary, Bristol, UK

Rho GTPases are key regulators of the actin cytoskeleton and stress fibre formation in smooth muscle. In human myometrium, activated RhoA forms a complex with Rho-kinase (ROCK), which phosphorylates and inhibits myosin phosphatase (MYPT), causing a calcium-independent increase in myosin light chain phosphorylation and tension (Ca2+ sensitisation). A new, small GTP-binding protein, Rhoi, can inhibit RhoA–ROCK interaction to reduce Ca2+ sensitisation. Using immunohistochemistry, immunoblotting and immunofluorescence, we tested the hypothesis that increased expression of Rhoi during human pregnancy may be implicated in the uterine quiescence that characterises gestation. We found a marked upregulation of Rhoi protein expression in pregnant myometrium relative to nonpregnant myometrium. This was associated with a loss of phosphorylated MYPT, suggesting a loss of ROCK activity during pregnancy. Rhoi-transfected myometrial cells showed a loss of stress fibres and a ‘rounding' phenotype. We conclude that upregulation of Rhoi may interfere with RhoA–ROCK inhibition of MYPT to mediate uterine quiescence during pregnancy.

Toll-like receptors and mechanism of labour

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R Youssef, S Bollapragada, F Jordan, A Young, JE Norman

Division of Developmental Medicine, University of Glasgow, Glasgow, UK

Increasing evidence indicates that inflammatory mediators play a crucial role in parturition. In this study, we hypothesised that toll-like receptors, which mediate inflammatory processes, might be upregulated in labouring human myometrium than in nonlabouring human myometrium.

Myometrial samples were collected from women undergoing caesarean sections at term before labour (n= 11), at term in labour (n= 11), preterm before labour (24–36 weeks) (n= 9) or preterm in labour (n= 5). RT-PCR (Taqman) analysis was performed to determine mRNA concentration. Immunohistochemical staining was used to localise TLR2 and TLR4 protein expression.

Mean values of both TLR2 and TLR4 mRNA expression were comparable in labouring versus nonlabouring myometrium both at term and preterm gestations. Expression of both TLR2 and TLR4 increased with increasing gestation. Mean value of TLR2 at term was 58.92 (SD = 77.56) versus 6.48 (SD = 17.06) at preterm (P= 0.005). For TLR4, mean value was 98.61 (SD = 170.12) versus 11.98 (SD = 22.12) (P= 0.03). TLR2 and TLR4 expression was more pronounced in peridecidual areas within the myometrium.

In contrast to our original hypothesis, TLR expression is upregulated with increasing gestation and not by onset of labour.

Could high cholesterol be the cause of dysfunctional labour?

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J Zhang

Department of Physiology, Obstetrics & Gynaecology, University of Liverpool, Liverpool, UK

Previously, we found that prolongation of labour in obese women was due to inefficient uterine activity. As obese pregnant women often have a dyslipidemia and this situation would be more severe at term, we hypothesised that elevated cholesterol will impair human myometrial contractions and those changes will be inversely correlated with body mass index (BMI).

The effects of cholesterol manipulation on spontaneously or oxytocin-stimulated contractions were determined in samples from hysterectomies (30) and term-pregnant (24) and labouring (24) uterus.

Enrichment of cholesterol significantly reduced phasic activity, while extraction of cholesterol potentiated it. Intracellular (Ca2+) changes underlie the contractile changes. The effects of cholesterol manipulation increased from nonpregnant < pregnant < labouring uterus. Increased BMI is associated with significantly decreased myometrial contractility. Extraction of cholesterol increased L-type calcium channels' entry and decreased the activity of K channels.

We suggest that cholesterol may contribute to uterine quiescence but may produce difficulties in labour in obese women.

Characterisation of the inflammatory response in pre-eclampsia using an in vitro whole blood lipopolysaccharide stimulation model

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JA Brewster, NM Orsi, N Gopichandran, E Cadogan, JJ Walker

Perinatal Research Group, University of Leeds, Leeds, UK

Objective: The pathogenesis of pre-eclampsia is considered partly related to an underlying inflammatory dysfunction. This study aimed to identify differences in the whole-blood inflammatory response of women with pre-eclampsia. Methods: Blood was collected from 20 women with pre-eclampsia and from matched controls. In vitro stimulation with bacterial lipopolysaccharide was performed; serial samples were taken at 0, 2, 6 and 24 hours and 17 cytokines were analysed by multiplex immunoassay.

Results: There were no significant differences in baseline or stimulated cytokine profiles between the two groups. When divided into early and late onset (</>34 weeks), there was a trend in all cytokines towards a lower secretory capacity in earlier gestations in both groups.

Conclusions: Pre-eclampsia was not associated with perturbations of the inflammatory response of whole blood in vitro. Gestation appears to play a role in modulating the inflammatory response in pregnancy, with a reduction in secretory capacity in earlier pregnancy.

Spindle assembly checkpoint dysfunction: a molecular correlate for human aneuploidy

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HA Homer,a,b,c,d A McDougall,b,e M Levasseur,b AP Murdoch,a,c M Herberta,c

a Newcastle Fertility Centre at Life, Royal Victoria Infirmary, Newcastle upon Tyne, UK b School of Cell and Molecular Biosciences, University of Newcastle, Newcastle upon Tyne, UK c School of Surgical and Reproductive Sciences, University of Newcastle, Newcastle upon Tyne, UK d Present address: Cumberland Infirmary, Carlisle, UK ePresent address: UMR 7009 CNRS / Université Pierre et Marie Curie (Paris VI), Observetoire Océanologique, 06230 Villefranche-sur-Mer, France.

Meiosis I errors (non-disjunction) in oocytes are responsible for 80–90% of human aneuploidies and are a major cause of Down syndrome, in vitro fertilisation (IVF) failure and miscarriage. Genes like BubR1, which encode components of a proofreading network called the spindle assembly checkpoint (SAC), are indispensable for averting non-disjunction in lower eukaryotes. Gene function had not been hitherto investigated in human oocytes. We used a mouse model and timelapse fluorescence imaging to circumvent limited oocyte availability and morpholino-based post-transcriptional gene silencing to examine gene function. We showed that depleting BubR1 levels in mouse oocytes increases aneuploidy from ∼1 to ∼40%. Human oocytes phenocopy mouse oocytes as they are capable of mounting an SAC response that is dependent upon BubR1. Interestingly, oocytes from an woman with IVF exhibited SAC fragility, suggesting a link between subfertility and SAC dysfunction. Together, these data indicate that defective oocyte SAC function is an important molecular correlate for human reproductive problems.

A trial of sequential therapy of imiquimod, followed by photodynamic therapy for vulval intraepithelial neoplasia

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U Winters,a,b A Tomlinson,a P Stern,b H Kitchenera

a University of Manchester, St Mary’s Hospital, Manchester, UK b Paterson Institute for Cancer Research, Manchester, UK

The aim of this phase I/II study was to demonstrate the tolerability of imiquimod and photodynamic therapy (PDT) used sequentially and to assess both lesion response and immunological response in women with vulval intraepithelial neoplasia (VIN).

VIN lesions were documented at baseline using measurements and photographs, and biopsies were obtained for histological grading, HPV typing and immunohistochemistry. Patients self-applied imiquimod, a topical immune response modifier, to their VIN lesions for 8 weeks. Two PDT treatments were delivered 1 month apart to a total of 100 joules/cm2 following application of the photosensitiser Metvix (Gardesma, Amersham, Bucks, UK).

Assessments of lesions after applying imiquimod and after PDT were made as at baseline. Symptomatic responses were recorded in patient diaries by means of visual analogue scales.

To date, 22 women have been recruited, of whom 9 have completed follow up until 26 weeks. Imiquimod has been well tolerated. Sequential use of PDT was tolerated as long as adequate analgesia is in place. Response rates were 9/16 (57%) complete and partial responses after imiquimod and 7/9 (78%) complete and partial responses after PDT.

Immunological data will be presented in conjunction with clinical results.

Prenatal diagnosis, clinical outcome and the genetic basis for renal tract duplication

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SM Whitten,a,b LS Chitty,a,b DT Wilcox,c,d M Bitner-Glindzicz,b S Malcolm,b AS Woolfc

a Fetal Medicine Unit, Elizabeth Garrett Anderson Hospital, London, UK b Unit of Clinical and Molecular Genetics and c Unit of Nephro-Urology, Institute of Child Health, London, UK d Departments of Paediatric Urology, Great Ormond Street Hospital and Guy’s and St Thomas' Hospital, London, UK

Duplex kidneys occurring in 0.8% of the general population are increasingly diagnosed on prenatal ultrasound and may give rise to chronic renal damage. This work aims to elicit the potential clinical implications of and molecular basis for renal tract duplication.

We correctly diagnosed 75% of fetuses (n= 66) suspected of having renal duplication by applying specific diagnostic criteria during prenatal sonography. Over half of these infants required heminephrectomy in the first 2 years of life due to recurrent sepsis or poorly differentiated renal function.

Renal sonography to screen families of 25 affected infants showed one-quarter of first-degree relatives to be affected (27/105), supporting the hypothesis that duplication has a genetic basis. Murine knockout models suggest a number of convincing candidate genes for ureteric duplication; however, molecular analysis of human homologues FOXC1, FOXC2 and SPRY1 showed no mutations in affected individuals. Duplex kidneys may be caused by mutations in several genes interacting at the ureteric bud during embryogenesis.

Use of the hCG ratio in the prediction of ectopic pregnancy and the success of conservative management strategies

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E Kirk, G Condous, Z Haider, T Bourne

Early Pregnancy, Gynaecological Ultrasound and Minimal Access Surgery Unit, St Georges Hospital, London, UK

Aim: To assess the use of hCG ratio (hCG 48 hours/hCG 0 hour) in the (1) prediction of ectopic pregnancy (EP) in asymptomatic pregnancies of unknown location (PUL) and (2) prediction of success of conservative management strategies for EP. (1) A total of 3996 women attended the Early Pregnancy Unit. About 388 women with PUL (9.7%) had hCG ratios calculated and were followed up until final clinical outcomes known. An hCG ratio of 0.8–1.6 was found to be optimal for diagnosis of EP. (2) In a group of 329 women with EPs, 98 were managed conservatively. About 72 of 98 women had hCG ratios calculated before treatment. Management was expectant or with single-dose methotrexate. hCG ratios were significantly different between those with successful and unsuccessful expectant and medical management (P < 0.05). Cutoff hCG ratios of 0.8 and 1.5–1.6 maximised the probability of success of expectant and medical management, respectively.

Conclusion: An hCG ratio can be used to predict EP and the likelihood of success of conservative management strategies.

Natural antimicrobial proteins in the amnion: defence against ascending infection?

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S Stock, J Brown, R Kelly, S Riley, A Calder

Department of Obstetrics and Gynaecology, University of Edinburgh, Edinburgh, UK

The fetus develops in the amniotic cavitythat is normally sterile. Infectious agents, which may ascend from the vagina, can threaten the wellbeing of the fetus and stimulate premature labour, the major cause of neonatal mortality. The amnion is critically positioned as the last line of defence between the fetus and the septic lower genital tract; yet, the innate immune responses of this tissue have been poorly characterised to date. We investigated the amniotic production of eight natural antimicrobial proteins found to be important in innate immunity of other epithelia. We found that human beta-defensin 2 (HBD2) was rapidly upregulated by stimulation with interleukin 1-beta, a cytokine associated with infection-driven preterm labour. HBD2 is a potent natural antibiotic, which also interacts with the adaptive immune system. We believe that it may have an important role in helping protect the fetus and preventing infection-induced preterm delivery.

The human oxytocin receptor is an acute-phase response gene regulated by NF-kB and C/EBP

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V Terzidou

Imperial College London Parturition Research Group, Institute of Reproductive and Developmental Biology, East Acton, London, UK

The increased myometrial sensitivity to oxytocin at term is mediated through increased oxytocin receptor (OTR) expression. In other species, OTR is upregulated by estrogen and downregulated by progesterone. The human OTR promoter does not, however, contain any consensus estrogen or progesterone response elements and there is no evidence of direct action of steroids on the OTR gene promoter. IL-1b concentrations increases within the uterus at the time of labour. OTR promoter contains putative transcription-factor-binding sites for AP-1, C/EBP and NF-kB. In this study, we showed that IL-1b induces an increase in OTR mRNA concentrations and OTR-specific ligand binding in myometrial cells, which is maximal at 4 hours and decreases after 20 hours. IL-1b activates each of the transcription factors AP-1 C/EBP and NF-kB. Using computer-based analysis and electromobility shift assay (EMSA) studies, we have identified three AP-1, nine C/EBP and two NF-kB DNA-binding sites in the OTR promoter. In transient transfection studies, OTR promoter activity was increased by C/EBPb and NF-kB but not by AP-1. C/EBPb and NF-kB together had a synergistic action in induction of OTR promoter activity. Site-directed mutagenesis of each individual C/EBPb and NF-kB sites had no effect upon the ability of either C/EBPb or NF-kB or the combination of both to activate OTR promoter. However, mutation of both the NF-kB sites inhibited promoter activation by NF-kB alone but not the combination of C/EBPb and NF-kB. Deletion studies showed that it is a region between −851 and −656 of the OTR that confers responsiveness to the combination of C/EBPb and NF-kB. Our data suggest that OTR may be considered to be a member of the family of ‘acute-phase response' genes, activated by cytokines and regulated by inflammatory transcription factors that are involved in the process of parturition.

Tests in the prediction of complications of pre-eclampsia: systematic review on the accuracy of proteinuria and uric acid

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S Thangaratinam,a K Ismail,a S Sharp,b A Coomarasamy,c F O’Mahony,a KS Khan,c PMS O’Briena TIPPS (Tests In Prediction of Pre-eclampsia’s Severity) review group

a Academic Unit of Obstetrics and Gynaecology, Keele University School of Medicine, University Hospital of North Staffordshire, Stoke-on-Trent, UK b NeLH Specialist Library for ENT and Audiology, Radcliffe Infirmary, Oxford, UK c Education Resource Centre, Birmingham Women’s Hospital, Birmingham, UK

Pre-eclampsia is associated with several maternal and fetal complications. At present, there are no robust systematic reviews or large studies on accuracy of tests that could predict complications in women with pre-eclampsia. The aim of this study was to determine the accuracy with which the most widely applied tests predict maternal and fetal complications in women with pre-eclampsia by systematic quantitative review of test accuracy studies. We conducted electronic searches in MEDLINE (1951–2004), EMBASE (1980–2004), the Cochrane Library (2004: Issue 4) and the MEDION database to identify relevant articles with no language restrictions. A two-generational Delphi method was used to prioritise the clinically relevant tests that are considered helpful in predicting maternal and fetal complications of pre-eclampsia. Sixteen tests were identified as clinically significant predictors of complications in pre-eclampsia, two of which, proteinuria and uric acid, are presented in this study. Twelve articles with 5766 women and 18 articles with 3913 women met the selection criteria for proteinuria and uric acid as predictors of complications of pre-eclampsia, respectively. The risk of eclampsia, abruption and perinatal death was found to be significantly increased (relative risk 3.0 [95% CI 2.7–3.3], 2.0 [95% CI 1.8–2.4], 1.9 [95% CI 1.7–2.0]) for proteinuria levels of more than 5 g/24 hour in women with pre-eclampsia of any severity. A positive test result of uric acid greater than or equal to a 360 μmol/l threshold predicted eclampsia, severe hypertension and perinatal deaths, with pooled likelihood ratios of 2.1 (95% CI 1.4–3.5), 1.7 (95% CI 1.3–2.2), 1.5 (95% CI 0.91–2.6), while a negative test result had a pooled likelihood ratio of 0.38 (95% CI 0.18–0.81), 0.49 (95% CI 0.38–0.64), 0.51 (95% CI 0.20–1.3), respectively. Hence, serum uric acid was identified as a poor predictor of either maternal or fetal complications and the risk of complications was increased for varying levels of proteinuria.

Compartmentation, function and expression of L-type calcium channel in human myometrium

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B Chanrachakul, AY Warren, RW Shaw, FB Pipkin, R Khan

Academic Division of Obstetrics and Gynaecology, School of Human Development, University of Nottingham, The Medical School, Derby City General Hospital, Derby, UK

Uterine contraction is modulated by calcium (Ca2+) influx through L-type Ca2+ channels (LTCC) and potassium (K+) efflux, in part, via Ca2+-activated K+ channels (BKCa). This study investigated possible coupling between LTCC and BKCa as well as the function and expression of LTCC in human myometrium. Myometrial biopsies were taken from nonpregnant and pregnant women following hysterectomy or caesarean section, respectively (ethics approval and informed consent obtained). LTCC expression, assessed by Western blotting, was upregulated in myometrium of pregnant women compared with those in the myometrium of nonpregnant women. Isometric recordings showed that the maximum contraction achieved by Bay K 8644, an LTCC agonist, was significantly higher in myometrium of pregnant women. Colocalisation and protein–protein interactions between LTCC and BKCa were demonstrated by double immunofluorescence and immunoprecipitation. These results provide evidence of coupling between LTCC and BKCa in human myometrium. Moreover, the upregulation of LTCC at term gestation suggests a role in the initiation of contractility at term.

Opportunistic screening for Chlamydia trachomatis (CT) in asymptomatic men

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S Sripada,a S McGillivray,a S Logan,a H Mckenzie,b M Hamilton,a A Sutherland,c C Morrison,d S Bhattacharyaa

a Department of Obstetrics and Gynaecology b Department of Microbiology and c Department of Orthopaedics, University of Aberdeen, Foresterhill, Aberdeen, UK d NHS Grampian, Aberdeen, UK

Despite the adoption of screening programmes in women, Chlamydia trachomatis (CT) infection rates continue to rise. High infection rates suggest that men may act as reservoirs, but recent national surveys have shown a low uptake of screening in men. We performed opportunistic screening on 1287 men attending a fracture clinic, a fertility clinic and a family planning clinic. The aim was to detect the prevalence of asymptomatic CT infection and to investigate the acceptability of urinary CT screening. The participation rate was 80% and the overall prevalence of CT was 4%, varying from 15% in men aged 20–24 years to 1% in men aged above 30 years. Prevalence was lowest in the fertility clinic (0.2%) and highest in the family planning clinic (14%). Decliners were more likely to have undergone previous screening (27 versus 17%, P= 0.01) and less likely to have harboured past infection (10 versus 31%, P= 0.04). Urinary CT screening was considered acceptable by 936 (91%) men. Asymptomatic young men attending hospital clinics have high rates of CT infection and may benefit from opportunistic screening.

Factors predisposing women to chronic pelvic pain: a systematic review

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P Latthe, L Mignini, R Gray*, R Hills*, K Khan

Academic Department of Obstetrics & Gynaecology, University of Birmingham, Birmingham, UK *Clinical Trials Unit, University of Birmingham, Edgbaston, Birmingham, UK

Objective: We evaluated factors predisposing women to chronic and recurrent pelvic pain (CPP), a common chronic condition.

Design, data sources and methods: Systematic review of all relevant studies without language restrictions was performed in Medline, Embase, PsycINFO, Cochrane Library, SCISEARCH, conference papers and bibliographies of retrieved primary and review articles. Two reviewers independently extracted data on study characteristics, quality and results. Results were pooled within subgroups defined by type of pain and risk factors.

Results: There were 122 studies (in 111 articles), of which 63 (64 286 women) evaluated 54 risk factors for dysmenorrhoea, 19 (18 601 women) evaluated 14 risk factors for dyspareunia and 40 (12 040 women) evaluated 48 factors for noncyclical pelvic pain. Presence of pelvic pathology, history of abuse and psychological morbidity were associated with all three types of pelvic pain. There were numerous other associations found for the different types of CPP.

Conclusion: A number of gynaecological and psychosocial factors are strongly associated with CPP. Randomised controlled trials of interventions targeting potentially modifiable factors are needed to assess their clinical relevance in CPP.

Inhibitory effect of leptin on human uterine contractility

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MP Hehir, AT Moynihan, SV Glavey, TJ Smith, JJ Morrison

Department of Obstetrics and Gynaecology, Clinical Science Institute, University College Hospital, Galway, Ireland

This study investigated the effects of leptin, the major secretory product of adipose tissue, on human uterine contractility in vitro. Biopsies of human myometrium were obtained at elective caesarean section (n= 18). Dissected myometrial strips suspended under isometric conditions, undergoing spontaneous and oxytocin-induced contractions, were exposed to cumulative additions of leptin in the concentration range of 1 nmol/l to 1μmol/l. Control strips were run simultaneously. Integrals of contractile activity were measured using the PowerLab hardware unit and Chart v3.6 software. Leptin exerted a potent and cumulative inhibitory effect on spontaneous and oxytocin-induced contractions, compared with control strips. The mean maximal inhibition values were as follows: 46.794 ± 5.133% (n= 6; P < 0.001) for spontaneous contractions and 42.323 ± 3.692% (n= 6; P < 0.001) for oxytocin-induced contractions. This physiological inhibitory effect of leptin on uterine contractility may play a role in the dysfunctional labour process associated with maternal obesity and the resultant high caesarean section rates.

The effect of interleukin-6 on tubal function as a contributing factor to endometriosis-related subfertility

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A Papathanasiou, O Djahanbakhch

Department of Obstetrics and Gynaecology, Bart’s and The London and Newham University Hospitals, London, UK

In this experimental in vitro study, we investigated the effect of interleukin-6 (IL-6) on the ciliary beat frequency (CBF) of the human fallopian tube by use of a well-established technique based on changes in light intensity. Ampullary mucosal explants were retrieved from the fallopian tubes of eight fertile women undergoing hysterectomy, and baseline CBF measurements were taken. Multiple concentrations of IL-6 (10 100 and 1000 pg/ml) were applied and CBF measurements were re-taken. Monoclonal anti-IL-6 antibody was then added and CBF measurements were repeated. Controls for possible mechanical or direct antibody effect were used. A repeated measures analysis of variance was used for statistical comparisons.

There was a significant decrease in the CBF when IL-6 was introduced at a concentration of 1000 pg/ml (mean difference 0.620 Hz, 95% CI 0.465–0.774, P < 0.05). This was followed by an increase towards the baseline levels after introduction of anti-IL-6 (mean difference 0.407 Hz, 95% CI 0.265–0.549, P < 0.05). Raised IL-6 concentrations have been reported in the peritoneal fluid of women with endometriosis. Similar concentrations of IL-6 inhibit ciliary activity. This study has demonstrated for the first time the importance of IL-6 on tubal transport and its potentially critical role in endometriosis-related infertility.

The impact of acquired thrombophilia on maternal and fetal wellbeing in a low-risk primigravid population

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SM Cooley,a JC Donnelly,a T Walsh,a J Gillen,a C Mc Mahon,b MP Gearya

a Rotunda Hospital, Dublin 1, Ireland b Our Lady’s Hospital for Sick Children, Crumlin, Dublin 12, Ireland

A total of 1011 primips were recruited. Serial thrombophilia screens were taken at booking, 36 weeks of gestation and 8 weeks postnatally. Ultrasounds were undertaken at 24 and 36 weeks of gestation for assessment of fetal wellbeing, placental morphology and umbilical and uterine artery dopplers. Detailed postnatal histological assessment of the placenta was performed in all cases. All mothers and infants were reviewed following delivery and 8 weeks later.

All data while collected prospectively were analysed retrospectively. About 175 positive test results have returned, giving an overall incidence of acquired thrombophilia of 18.2%. The seroconversion rate over the course of their pregnancy was 70%.

The impact of positive serology was further investigated and correlated with antenatal placental and Doppler morphology, antenatal and intrapartum events and obstetric outcome. Positive serology was significantly associated with increased maternal blood loss at delivery and increased neonatal intensive care admissions (P < 0.01).

Haemodynamic and biochemical markers of pre-eclampsia

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C Cuckson, L Poston, A Shennan

Division of Reproductive Health, Endocrinology and Devleopment, King’s College, London, UK

Women should be assessed for risk of pre-eclampsia to allow a schedule of antenatal care and management to be tailored. This study evaluated the prediction potential of promising biochemical and haemodynamic markers to predict pre-eclampsia. About 172 women were recruited with risk factors for pre-eclampsia. Sixteen women developed pre-eclampsia. Samples, digital volume pulse (DVP) and sphygmocor readings were taken at 11–14 weeks of gestation and then at 15–17, 19–21 and 23–35 weeks. DVP and sphygmocor data showed no association with pre-eclampsia. Receiver operator curve (ROC) areas and positive predictive value (PPV) for significant predictors were: Doppler (0.69/0.59), blood pressure (0.81/0.63), free placental growth factor (0.7/0.63), matrixmetalloproteinase-9 (0.59/0/14), soluble tumour necrosis factor-alpha receptor-1 measurements (0.74/0.47), plasminogen activator inhibitor-2 (0.62/0.55). Soluble Flt-1 and leptin were not significant predictors. This data suggest that good predictive powers can be achieved for 16, 20 and 24 weeks of gestation. Combining haemodynamic and biochemical measures only marginally improves prediction.

Loss of the extracellular matrix protein TGFBI induces clinical paclitaxel resistance, mitotic spindle abnormalities and centrosome amplification

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AA Ahmed, AD Mills, C Blenkiron, CE Massie, M Vias, N Gopalakrishna, R Crawford, H Earl, R Laskey, C Caldas, JD Brenton

Gynaecological Oncology Unit, Addenbrookes Hospital and University of Cambridge, Cambridge, UK

We report here that loss of the extracellular matrix (ECM) protein TGFBI (transforming growth factor beta induced) was sufficient to induce paclitaxel resistance in ovarian cancer cells. Loss of TGFBI caused severe mitotic spindle abnormalities and centrosome amplification in interphase cells consistent with a failure of mitotic checkpoints. TGFBI expression was significantly (P= 0.0087, Wilcoxon test) lower and associated with centrosome amplification (P= 0.019, Wilcoxon test) in paclitaxel-resistant tumour samples from a prospective ovarian cancer therapy trial. These data show that loss of an ECM protein causes paclitaxel resistance via disruption of mitotic checkpoints. TGFBI is therefore an attractive target for therapeutic intervention and may be an important predictor of taxane response in ovarian cancer patients.

Neurological developmental variations in assisted conception and spontaneous pregnancies

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J Joy,a C Patterson,b N McClure,a P Hepper,c I Cookea

a Obstetrics and Gynaecology, Institute of Clinical Science, Queen’s University Belfast, Grosvenor Road, Belfast, UK b Epidemiology and Public Health, Queen’s University Belfast, Belfast UK c School of Psychology, Queen’s University Belfast, Belfast, UK

Habituation, defined as decrement in response following repeated stimulation with the same stimulus, indicates an intact central nervous system. Habituation, taken as a measure of neurological development, was used to compare fetuses conceived by artificial reproductive technologies (ART) with naturally conceived (NC) gestation-matched fetuses. Sound stimuli (250 Hz, 110 dB) were administered at 10-second intervals for 2 seconds. Habituation (cessation of all movement for five consecutive stimuli) was observed with ultrasound and video recorded. Tapes were blinded and analysed with a standardised scoring sheet. Significantly, more fetuses in the ART group responded to 250 Hz. Of the responders, there was no difference in habituation. Startle, assessed by comparing the magnitude of first response to 250 Hz in terms of amplitude, latency, speed and body parts moved, was significantly higher in ART group. After adjustment for potential confounders, the differences remained significant. Fetuses conceived by ART demonstrate no evidence of neurodevelopmental delay in utero compared with NC fetuses.

Retargeting adenovirus gene therapy via the epidermal growth factor receptor

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J Morrison,a S Briggs,b A Hale,b N Green,c C Herbert,c K Fisher,b S Kehoe,a LW Seymourb

a Nuffield Department of Obstetrics and Gynaecology and b Department of Clinical Pharmacology, University of Oxford, UK cHybrid Systems Ltd, Upper Heyford, Oxfordshire, UK

Intraperitoneal adenovirus cancer gene therapy is limited in clinical trials by low tumour cell transduction efficiency (due to low Coxsackie adenovirus receptor (CAR) expression in many ovarian tumours) and host immune responses. Epidermal growth factor receptor (EGFR) is overexpressed in 60% of ovarian tumours and is an attractive candidate for re-targeting adenovirus infection.

Normal tropism of adenovirus was ablated by covalent linkage of a polymer based on poly[N-(2-hydroxypropyl)methacrylamide] (pHPMA). Murine epidermal growth factor (EGF) was attached to polymer to restore infectivity; biological activity of EGF was maintained.

EGF-polymer-coated adenovirus (EGF-pc-Ad), while showing no greater transduction of the parental cells, showed significantly improved transduction of EGFR-positive cell lines derived from the CAR-negative murine fibroblast cell line A9. EGF-pc-Ad transduction could be inhibited by a blocking anti-EGFR antibody but not in CAR-positive A9 clones. Similar results were demonstrated in EGFR-positive tumour cell lines. Blocking anti-CAR antibody or excess free fibre had no effect on EGF-pc-Ad.

Does the urethral sphincter change with advancing age?

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P Rahmanou, C Chaliha, V Khullar

Department of Urogynaecology, St Mary’s Hospital, Imperial College, London, UK

Continent women have a decrease in the urethral length and maximum urethral pressure with increasing age. It has been hypothesised to be due to a loss of urethral striated muscle as women age.

Women with lower urinary tract symptoms without previous continence procedures were studied. Urodynamics was performed and then they had a transperineal 3D ultrasound urethral scan. The striated and core smooth muscle volumes were calculated for the urethral sphincter. The volumes were correlated with age using Pearson correlation.

Forty-seven women recruited with different urodynamic diagnosis. Ten were diagnosed with detrusor overactivity (DOA), 18 had urodynamic stress incontinence (USI), 10 with mixed incontinence, 2 had voiding difficulty and 7 with normal urodynamic study. The study showed a significant decrease in striated sphincter volume in women with DOA (r= 0.7, P= 0.024) and urethral length with increasing age.

This study confirms decreasing striated muscle volume with increasing age in women with DOA only. These changes were not seen in those with other urodynamic diagnosis.

Gene transfer to human fetal tissues in vitro

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A David,a B Weisz,a A Ruthe,b DM Peebles,a C Coutelle,b CH Rodeck,a M Themisb

a Department of Obstetrics & Gynaecology, University College London, London, UK b Gene Therapy Research Group, Imperial College, London, UK

Prenatal gene therapy may offer advantages over adult treatment of genetic diseases by preventing early disease manifestation, targeting stem cells and avoiding immune sensitisation. Studies in haemophilia B transgenic fetal mice show proof of principle for cure. We assessed the efficiency of gene transfer to human fetal tissues in vitro.

Fetal tissues were collected at surgical termination of pregnancy (n= 6; 7–13 weeks of gestation) and incubated overnight with adenovirus (8.8 × 1010 particles) or HIV (1 × 108 particles) vectors containing the lacZ or GFP transgenes. Transgene expression was detected using X gal staining or fluorescent microscopy.

Adenovirus gave high levels of transgene expression in the fetal liver and muscle, with weaker expression seen in the skin, adrenal and heart. Low-level expression was detected in the fetal liver after HIV application.

Human fetal tissues can be transfected in vitro. Future work will examine toxicity and insertional mutagenesis.

The death of academic Obstetrics & Gynaecology in the UK?

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AL David, SM Whitten, CH Rodeck

Department of Obstetrics & Gynaecology, University College London, London, UK

Academic training posts in Obstetrics & Gynaecology (O & G) have fallen by 24% in the past 2 years. Academic O & G is under pressure from the Research Assessment Exercise, while overall recruitment into the specialty is critically low. Is there a future for scientific and clinical progress in O & G in the UK? We surveyed the academics of the future for their views on training and opportunity in academia.

Of 26 medical schools, 7 had no O & G academic trainees, with several posts being lost in the past 5 years. Forty-seven percent of trainees were wholly university funded, but in 26% of posts, the NHS funded half the salary. One-quarter of trainees had no recognised mentor. Trainees identified the following issues to improve the career: a clear academic career structure, more flexible clinical training, protected time for research and recognition for teaching activities. Clear initiatives are needed to improve the O & G academic training pathway.

Observational study of the influence of duration of coasting and drop in serum estradiol levels on IVF outcome

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C Kailasam, P Wilson, H Collyer, J Jenkins

Centre for Reproductive Medicine, University of Bristol, Bristol, UK

Objective: To assess prognostic value of duration of coasting and drop in serum estradiol (E2) levels on in vitro fertilisation (IVF) outcome.

Design: Observational study of 2775 cycles of IVF/intra cytoplasmic sperm injection (ICSI). About 291 cycles were coasted to reduce the risk of ovarian hyperstimulation syndrome (OHSS).

Materials and methods: Long gonadotrophin-releasing hormone agonist downregulation protocol, with initial FSH dose of 150 iu (women <35 years) and 300 iu (women ≥35 years). E2 levels were monitored if ≥20 follicles and coasting initiated depending on E2 levels once leading three follicles ≥15 mm. hCG was administered when E2 levels were <15 000 pmol/l. Cycles proceeding to oocyte retrieval were analysed for oocyte maturity, normal fertilisation rate, implantation rates and pregnancy rates. Results: A total of 291 coasted cycles were analysed. About 217 cycles proceeded to egg collection. Percentage of mature eggs from day 1 through day 6 of coasting ranged from 80 to 95% and percentage of normally fertilised eggs ranged from 60 to 79%. Implantation rates from days 1 to 6 of coasting ranged from 11 to 50% and pregnancy rates ranged from 20 to 71%. Treatment outcome in relation to percent drop in E2 levels from the day prior to hCG administration was analysed. The maximal E2 drop was 45%. Percentage of mature eggs ranged from 83 to 90% and percentage of normally fertilised eggs ranged from 62 to 63%. Implantation rates ranged from 10 to 29% and pregnancy rates ranged from 22 to 46%.

Discussion: No significant difference in the proportion of mature eggs retrieved, normal fertilisation rate, implantation rate and pregnancy rates irrespective of coasting duration and drop in E2 levels within this study was observed.

Conclusion: Treatment outcome remained good, irrespective of duration of coasting and fall in E2 levels within the limits of our protocol, which were essentially arbitrary; hence, further research is required to determine whether these could be extended.

Protein expression in human granulosa cell subtypes

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DJ Gillott,a A Eldib,a E Iammarrone,a,b AH Handyside,b JG Grudzinskasa,b

a Reproductive Physiology Laboratory, St Bartholomew’s Hospital, London, UK b The London Bridge Fertility, Gynaecology and Genetics Centre, London Bridge, London, UK

Mural and cumulus granulosa cells (mGC & cGC) were isolated from women undergoing controlled ovarian hyperstimulation for in vitro fertilisation (IVF)/intra cytoplasmic sperm injection (ICSI) before in vitro culture. Metabolic labelling using l-[35S]-methionine was employed in some cases. Two-dimensional gel electrophoresis was performed on the cellular proteins, and resulting gels were visualised by phosphoimaging or silver staining. Semiquantitative computerised analysis of the gels revealed 856 (±190) spots per gel. Several protein spots with molecular weight between 25 and 60 kDa and isoelectric points between pH 4.5 and 6 were identified as being unique to either cGC or mGC. These results show the constitutive and biosynthetic proteomes of human granulosa cells. The experimental techniques we have established may enable the isolation of GC subpopulations or correlation of GC protein expression with the fertilisation outcome and embryo development. This experimental model may be used to assess the molecular effects of known endocrine, autocrine and paracrine factors that may influence follicular development.

Is the ultrasonographic appearance of an ectopic pregnancy a predictor of success for conservative management strategies?

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E Kirk,a G Condous,a Z Haider,a B Van Calster,b D Timmerman,b T Bournea

a Early Pregnancy, Gynaecological Ultrasound and MAS Unit, St Georges Hospital, London, UK b Department of Obstetrics and Gynaecology, University Hospital Gasthuisberg and Department of Electrical Engineering (ESAT), KU Leuven, Belgium

Ninety percent of ectopic pregnancies (EPs) are visualised on transvaginal ultrasound (TVS), but can the specific appearance of the EP predict the outcome from conservative management? Data were collected prospectively on women with EP managed expectantly or medically with methotrexate. All women were followed up until success of treatment known. The size and morphology of the EP masses were recorded. The TVS appearances in the expectantly managed group were the following: 35 (90%) inhomogeneous masses, 2 (5%) empty gestational sacs and 2 (5%) sacs with fetal poles. In the medically managed group, there were 40 (68%) inhomogeneous masses, 17 (29%) empty gestational sacs and 2 (3%) sacs with fetal poles. There was no significant difference in size (P > 0.5) or morphology (P > 0.5) of the EP mass between those with either successful or unsuccessful expectant or medical management. Conclusion: The ultrasonographic appearances and size of EPs do not seem important in predicting likely success of conservative management.

Can we reduce the number of follow-up visits for pregnancies of unknown location?

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E Kirk, G Condous, Z Haider, T Bourne

Early Pregnancy, Gynaecological Ultrasound and Minimal Access Surgery Unit, St Georges Hospital, London, UK

A continuing prospective study to try and reduce the number of visits for women with pregnancies of unknown location (PUL). hCG levels are taken at 0 and 48 hours and entered into a logistic regression model to give a predicted outcome. Women are managed according to the prediction. Women with intrauterine pregnancies (IUPs) and ectopic pregnancies (EPs) return on day 7 for repeat scan and hCG levels if indicated. Failing PUL have repeat hCG on day 7. A total of 247 women have been managed according to the model. Model predicted failing PUL, IUPs and EPs, with sensitivities of 93, 79 and 74%, respectively. For failing PUL, mean time until diagnosis is 2.4 days (range 2–9 days). For IUPs, mean time until diagnosis is 7.7 days (range 2–14 days). For EPs, mean time until diagnosis is 8 days (range 2–26 days). Conclusion: Use of this model will potentially reduce the number of follow-up visits for women with PUL, who are at low risk of EP.

Analysis of methylation of CpG islands in ovarian cancer

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C Hardie,a JM Teodoridis,a J Hall,a J Curto,a N Siddiqui,b R Browna

a University of Glasgow, Centre for Oncology and Applied Pharmacology, CRUK Beatson Laboratories, Glasgow, Scotland, UK b Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow, Scotland, UK

Aberrant methylation of CpG islands (CGI) occurs frequently in cancer and is associated with transcriptional silencing of flanking genes. Epigenetic inactivation of genes may contribute to tumorigenesis and can affect tumour properties such as chemoresistance. CGI methylation can be easily detected by methylation-specific PCR. We analysed methylation of 24 CGIs in 142 epithelial ovarian cancers in order to assess its use as a diagnostic as well as predictive tool. In early-stage tumours, we identified genes that are frequently methylated and have potential use as early diagnostic markers (HIC1, MINT25, OPCML). In late-stage tumours, methylation of either BRCA1, GSTpi or MGMT correlates with improved response to chemotherapy (P= 0.013). This demonstrates the diagnostic as well as predictive potential of CGI methylation analysis.

The Ser373Tyr polymorphism in the D6 chemokine decoy receptor is not associated with development of preeclampsia or offspring birthweight

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B Pearce,a J Madigan,b A Brown,a I Greer,a R Nibbs,b D Freemana

a Divisions of Developmental Medicine and b Immunology, Infection and Immunity, University of Glasgow, Glasgow Royal Infirmary, Glasgow, UK

D6 is a decoy receptor for proinflammatory chemokines that limits inflammation. It is abundantly expressed on trophoblasts and may regulate the inflammatory responses at the maternal–fetal interface. D6 dysfunction may contribute to pre-eclampsia. The D6 gene contains a Ser to Tyr substitution at aminoacid 373 (S373Y) in a domain of the protein that controls D6 stability and internalisation. The aim was to determine whether this polymorphism was associated with risk of pre-eclampsia or low birthweight. S373Y genotype was determined by allelic discrimination in a case (n= 153)–control (n= 308) study. Relative to the common YY genotype, neither the SY (OR [95% CI]: 1.44 [0.92–2.25]; P= 0.11) nor the SS genotype (OR [95% CI]: 1.16 [0.63–2.13]; P= 0.64) was associated with pre-eclampsia. There were no differences between the proportions of low (<20th centile) and higher birthweight (>20th centile) babies for each genotype. Thus, the S373Y polymorphism does not contribute to the aetiology of pre-eclampsia or low birthweight.

RhoB GTPase mRNA and protein expression in human myometrial and placental tissues

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J Lartey,a A Gampel,b J Pawade,c H Mellor,b A López Bernala

a University of Bristol, Clinical Sciences South Bristol, Division of Obstetrics and Gynaecology, Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Bristol, UK b University of Bristol, Department of Biochemistry, School of Medical Sciences, University Walk, Bristol, UK c University of Bristol, Department of Pathology, Bristol Royal Infirmary, Bristol, UK

Rho GTPases are small monomeric proteins that play a key role in the regulation of the actin cytoskeleton. Transfection of activated RhoA and RhoB into quiescent fibroblasts induces the formation of actin contraction stress fibres. We and others have demonstrated a functional RhoA pathway in human myometrium, which can be activated by oxytocin and other stimulatory agonists. We aim to quantify RhoA and RhoB mRNA and protein expression and localisation in nonpregnant and pregnant term and preterm myometrial and placental tissues, using quantitative RT-PCR, immunoblotting and immunohistochemistry. We found an upregulation of RhoA and RhoB mRNA expression in pregnant myometrium relative to nonpregnant myometrium. There were similar protein expression levels of RhoA and RhoB in nonpregnant and pregnant term and preterm myometrium. RhoB demonstrated a cytoplasmic distribution with perinuclear enhancement of myometrial cells, placental trophoblasts and decidual cells. This is the first description of RhoB GTPase mRNA and protein expression in human myometrial and placental tissues.

Stage III malignant mixed mullerian tumour of the fallopian tube. Report of a case with 13-year survival after recurrence following radical surgery and chemotherapy

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J Lartey,a J Nieto,b R Woolasc

a University of Bristol, Clinical Sciences South Bristol, Division of Obstetrics and Gynaecology, Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Bristol, UK b Norfolk & Norwich University Hospital, Norwich, UK c St Mary’s Hospital, Portsmouth, UK

A 40-year-old white woman presented with a history of vaginal discharge, abdominal pain and adnexal mass. Pelvic ultrasound revealed a 6-cm left adnexal mass of mixed echogenicity extending into the uterus. Haematological, biochemical and chest X-ray findings were normal. Exploratory laparotomy revealed a swollen left fallopian tube, with tumour extending into the pouch of Douglas. She underwent a total abdominal hysterectomy, bilateral salpingo-oopohrectomy, sigmoid resection and maximal tumour debulking. Histology revealed epithelial layers of adenocarcinoma and stromal areas of chondrosarcoma. Postoperatively, she was treated with six courses of adriamycin. Seven months later, she presented with a recurrence of an abdominal mass and was treated with additional courses of cisplatinum, ifosamide and mesna and further tumour debulking. She has remained disease free for 13 years. This case supports the case for platinum-based chemotherapy and optimal tumour debulking for recurrent tumour deposits. These rare cases with usually poor prognosis should be treated in specialist centres to optimise survival.

Pregnancy outcomes after false-positive midtrimester multiple marker screening tests (MMTS) for aneuploidy

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J Lartey,a M Hamisa,b R Guirgisb

a University of Bristol, Clinical Sciences South Bristol, Division of Obstetrics and Gynaecology, Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Bristol, UK b St Mary’s Hospital, Portsmouth, UK

We wanted to determine whether pregnancies with false-positive midtrimester multiple-marker screening tests (MMST) are associated with increased pregnancy complications. Adverse pregnancy outcomes (preterm delivery, low birthweight (LBW), fetal loss >20 weeks of gestation, APGAR <7 at 5 minutes, operative deliveries, congenital infections and abnormalities) in 211 pregnancies with false-positive MMST were compared with a control group of 300 women with low-risk MMST results. Chi-square analysis and Fisher’s tests were used for comparison. Preterm delivery is 5.6 versus 4.6%, OR 1.2 (95% CI 0.56–2.7); LBW is 2.3 versus 1.6%, OR 1.5 (95% CI 0.43–5.3); instrumental delivery is 9.4 versus 7.3%, OR 0.85 (95% CI 0.46–1.6); caesarean section is 21.3 versus 17%, OR 1.3 (95% CI 0.84–2.1) and APGAR at 5 minutes <7 is 5.6 versus 5.6%, OR 0.88 (95% CI 0.39–2.0). No fetal loss or congenital infections occurred. We conclude that women with a false-positive MMST and a normal midtrimester obstetric sonogram are not at an increased risk of pregnancy complications and adverse fetal outcomes.

Maternal thinness is associated with altered fetal kidney size and shape in late gestation

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K Mukherjee,a M Hanson,a J Poole,b S Crozier,b H Inskip,b K Godfrey,a,b the Southampton Women’s Survey Study Group

a Centre for Developmental Origins of Health and Disease and b MRC Epidemiology Resource Centre, University of Southampton, Southampton, UK

We hypothesised that impaired renal growth in utero could underlie the association between maternal thinness and raised offspring blood pressure. In the Southampton Women’s Survey, the mother’s height and skinfold thicknesses have been measured before pregnancy. At a mean (10th–90th centiles) gestation of 241 days (236–244 days), we measured fetal kidney length and derived cross-sectional area from width and anteroposterior diameters (right kidney: n= 520, left kidney: n= 529). Taller mothers tended to have fetuses with greater right and left kidney length (both P= 0.004). Thinner mothers with lower triceps skinfold thickness before pregnancy tended to have fetuses with smaller kidney cross-sectional area (P= 0.01 for both kidneys) and a lower area/length ratio (P= 0.03 for both kidneys), in other words ‘sausage-shaped' kidneys. This may reflect lower nephron numbers and supports the hypothesis that impaired renal growth may in part underlie the link between maternal thinness and raised offspring blood pressure.

Ovarian hormones and markers of oxidative stress in women undergoing assisted conception

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M Appasamy,a S Muttukrishna,a NP Groome,b P Serhal,a E Jauniauxa

a Department of Obstetrics and Gynaecology, Royal Free University College Medical School, London, UK b School of Biological and Molecular Sciences, Oxford Brookes University, Headington, Oxford, UK

The strongest predictors of successful outcome for women undergoing assisted reproductive treatment are age and the number of oocytes collected. Our objective was to study the relationship between ovarian hormones and markers of oxidative stress in women undergoing assisted conception. As a part of a prospective cohort study, 122 women undergoing assisted conception for various causes for infertility were studied. Serum and follicular fluid (FF) samples were collected on the day of oocyte recovery. Samples were analysed for inhibin A, inhibin B, anti-mullerian hormone (AMH) and estradiol (E2) levels using enzyme-linked immunosorbent assay. Plasma and FF samples were analysed for total antioxidant capacity (TAC) using calorimetric microplate assay. FF E2 levels positively correlated with the TAC in the FF (P < 0.001, r= 0.50). Serum E2 levels on the day of egg collection positively correlated with the number of oocytes collected (P= 0.001, r= 0.60) and the number of oocytes fertilised (P < 0.05, r= 0.50). There was no significant correlation between serum inhibin A, inhibin B or AMH and TAC in plasma as well as FF inhibin A, inhibin B or AMH with TAC in the FF. Low FF antioxidant capacity in women with low FF E2 suggests a change in the oxidative/ antioxidant balance, which could result in poor response to stimulation in women undergoing assisted conception.

Coeliac disease (CD) affects pregnancy outcome

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A Naheed, JD Aplin, PN Baker

Division of Human Development, The Medical School, University of Manchester, Manchester, UK

Coeliac disease (CD) is prevalent in 1 in 70 pregnancies. CD-associated adverse pregnancy outcomes have been reported, but the data are conflicting. A questionnaire was completed retrospectively for 141 pregnancies with a histological proven CD, regarding four indices of pregnancy outcome. This study investigated the hypothesis that gluten-free diet (GFD) reduces or abolishes the risk of CD-associated poor pregnancy outcome. Risk of preterm labour was found to be decreased in women with CD after GFD, as compared with untreated CD, but this did not achieve statistical significance. The risk of intrauterine growth restriction (IUGR) was significantly reduced after GFD (P= 0.0001). No difference was observed in risk of miscarriages and stillbirths before or after GFD. This study has established that GFD significantly reduced CD-associated IUGR.

Feasibility of early fetal echocardiography in an Irish setting

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N Russell,a F McAuliffea,b

a National Maternity Hospital, Dublin, Ireland b UCD Department of Obstetrics & Gynaecology, Dublin, Ireland

Background: Fetal echocardiography is increasingly being described early in pregnancy. Early fetal heart examination may provide early reassurance/early diagnosis for parents. In addition, it allows the natural progression of cardiac lesions to be assessed, an area poorly understood. We were interested in assessing the feasibility of early fetal echocardiography in our patient population.

Aim: To evaluate the feasibility of a fetal cardiac examination prior to 16 weeks of gestation.

Methods: This is a prospective study of 27 early fetal echocardiograms. All studies were performed transabdominally. The mean gestational age was 14 weeks of gestation (range 12 + 3 to 15 + 6). The satisfactory visualisation of cardiac anatomy was recorded.

Results: The mean crown-rump length (CRL) was 81 mm. In all cases, the four-chamber view was obtained and tricuspid and mitral valves adequately seen. Ascending aorta and main pulmonary artery was visualised in 22 cases (81%), although the branch pulmonary arteries were only identified in five (18%). The aortic and ductal arches were identified in 23 cases (85%) and the inferior vena cava/superior vena cava (IVC/SVC) visualised in 26 (96%). Overall, a satisfactory cardiac examination as defined by adequate visualisation of the four-chamber view, AV valves and outflow tracts was feasible in 22 cases (81%).

Conclusions: The results from this small cohort suggest that the fetal heart can be examined transabdominally early in pregnancy.

Pre-operative MR imaging in endometrial carcinoma: implications for Calman-Hine decision-making

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R Bhalla, Y Tapper, L Berger, J Crow, R Hadwin, H Evans, P Walker

Royal Free Hospital, London, UK

Endometrial cancer is the second most common gynaecological malignancy in UK. Calman-Hine guidelines stress the correct selection of patients to improve the outcome. Preoperative magnetic resonance imaging (MRI) may be useful in planning patient management. This study was an observational retrospective study over 7 years to assess the efficacy of MRI in preoperative staging of endometrial cancer. Sixty-four women fitting the criteria with a confirmed diagnosis of endometrial cancer on biopsy had their MRI staging compared with final histology. MRI correctly staged the disease in 56.3% of cases. Major discrepancies affecting management occurred in 15 women (23.4%). Cervical involvement was missed in nine (14.0%), lymph node involvement in six (9.4%) and depth of invasion incorrect in ten (15.6%). In 30 cases with predicted stage Ia/b, MRI underestimated stage in 50%, which would have changed the location of primary surgery. This study highlights the limited ability of MRI alone in accurately predicting the stage of disease.

Reactive oxygen species induce morphological and biochemical features of apoptosis in human trophoblast

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SJ Moll, I Crocker, CJP Jones, PN Baker, CP Sibley, AEP Heazell

Division of Human Development, University of Manchester, Manchester, UK

Pre-eclampsia is associated with increased apoptotic cell death in villous trophoblast. In addition, pre-eclampsia is associated with increased production of reactive oxygen species (ROS). ROS can induce apoptosis in cell studies. We hypothesised that ROS in the form of hydrogen peroxide (H2O2) would induce apoptosis in villous trophoblast. Placental villous explants from normal term placentas (n= 6) were cultured for increasing incubation periods (0–48 hours), with increasing concentrations of H2O2 (0–1000 μM), at 6% oxygen. Villous morphology and TdT-mediated dUTP nick end labelling (TUNEL) were assessed from semithin tissue sections and wax-embedded tissue, respectively. Apoptosis, quantified by TUNEL, showed a significant dose-dependent increase when explants were cultured in the presence of H2O2, an effect most pronounced at 6 hours with 1000 μM of H2O2. Morphological changes of apoptosis were seen in trophoblast including pyknotic nuclei, syncytial knots and cytoplasmic condensation. We conclude that morphological and biochemical markers of apoptosis are induced in normal villous trophoblast in the presence of ROS.

The Word catheter—an alternative treatment of Bartholin’s abscess

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Z Haider, E Kirk, M Alkatib, A Syed, T Bourne

Acute Gynaecology and Early Pregnancy and MAS Unit, St George’s Hospital, London, UK

Introduction: Bartholin’s abscesses are a common gynaecological problem. Current treatment practice in the UK is marsupialisation under general anaesthetic. In North America, a Word catheter is inserted in the outpatient clinic using local anaesthetic.

Method: A Word catheter was offered to women with a Bartholin’s abscess (December 2004–September 2005). Women were followed up at 1 week and then at 4 weeks (when catheter removed). While the catheter was in situ, the women completed charts to indicate pain, discharge and inconvenience experienced.

Results: Fifteen of the 20 women were successfully treated (four catheters fell out and one failed insertion). Most women were pain free within 1 week of insertion, felt unrestricted, would have another one if recurrence and would recommend the use of the catheter to a friend if they had a Bartholin’s abscess. None of these women had a recurrence (longer follow-up time would be preferable).

Conclusion: A Word catheter should be offered to women with a Bartholin’s abscess as a conservative alternative to marsupialisation.

Transvaginal scan (TVS) versus TVS and saline infusion hydrosonography for the diagnosis of endometrial polyps and submucous fibroids

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Z Haider, E Kirk, M Alkatib, A Syed, T Bourne

Acute Gynaecology and Early Pregnancy and MAS Unit, St George’s Hospital, London, UK

Introduction: This study investigates the accuracy of transvaginal ultrasound (TVS) alone and TVS with saline infusion hydrosonography (SIS) for visualising polyps and fibroids compared with hysteroscopy.

Method: This is a continuing prospective observational study. Women referred for hysteroscopy have TVS followed by SIS.

Results: A total of 75 women were recruited. Fifty-five have had TVS, SIS and hysteroscopy. Mean age was 44 years. At hysteroscopy, 24 polyps and 10 submucous fibroids were found. Thirteen of the 24 polyps were diagnosed with TVS alone and 20 of 24 with SIS. Four of the 10 fibroids were confirmed using SIS and five lesions thought to be polyps on SIS were fibroids. SIS overdiagnosed intracavity pathology. Seven lesions suspected with SIS were not confirmed at hysteroscopy. In 4 of the 7 cases, the endometrium was thickened or polypoid in nature. Four polyps seen at hysteroscopy were missed on TVS and SIS.

Conclusion: SIS is a helpful adjunct to the TVS for revealing intracavity pathology. This study reveals that it is not easy to clarify whether the pathology is fibroid or polyp, and polypoid, thickened endometrium or endometrial folds may be misinterpreted as lesions.